Heretofore, various sulfonylurea derivatives and biguanide derivatives have been widely used as oral hypoglycemic agents for lowering blood sugar values. However, these agents had disadvantages of causing serious hypoglycemic coma and lactic acidosis revelation, and therefore every possible care must have been taken for practical use. "Chem. Pharm. Bull., vol. 30, p. 3563 (1982)", "J. Med. Chem., vol. 32, p. 421 (1989)", "J. Med. Chem., vol. 34, p. 318 (1991)", "J. Med. Chem., vol. 33, p. 1418 (1990)", Japanese Unexamined Patent Publication No. 64586/1980, and European Laid Open Patent Publications No. 177353, No. 283035, No. 283036, No. 332331, No. 332332 and No. 605228 disclose various thiazolidindiones which achieve a hypoglycemic effect, and these are particularly useful for treating Type II diabetes and are noted as agents for hardly causing such hypoglycemic symptoms as caused by the above-mentioned oral hypoglycemic agents. However, although these compounds have a function of effectively lowering a blood sugar value, but it is not proved that these compounds have effects for reducing or preventing various chronic symptoms caused by diabetes, such as diabetic nephropathy, diabetic cataract, diabetic retinopathy, diabetic neuropathy and the like.
On the other hand, non-enzymatic glycosylation of vital protein has been recently noted for causing various diseases accompanied by diabetes and arteriosclerosis. Generally, the reaction of reducing sugars with amino acids and proteins caused by heat treatment of foods or during storing foods is known as Maillard reaction. It was recognized in 1970's that the Maillard reaction is actually caused in a living body, and this reaction is recently called as glycation (see "J. Biol. Chem., vol. 252, p. 2998 (1977)"). Also, it has been proved that glycation is exacerbated in such chronic hyperglycemic state as in diabetes, and it is presumed that the glycation becomes a trigger for causing various diabetic complications (see "New Eng. J. Med., vol. 314, p. 403(1986)"). The process of glycation is not completely clear, but it is considered that various vital proteins are reacted with reducing sugars to non-enzymatically form Schiff base, and that this is crosslinked after causing Amadori rearrangement and is converted to fluorescent browning materials, i.e. AGE (advanced glycosylation end products). It was recognized in rat's diabetic cataract that glycation of crystallin of lens protein is exacerbated. Also, it is presumed that glycation of myelin protein causes diabetic neuropathy and that glycation of collagen and elastin present in connective tissue causes renal dysfunction-inducing thickening of renal glomerular basement membrane and atherosclerosis. Brownlee et al reported that the anti-glycation effect of aminoguanidine prevents formation of AGE protein on arterial walls of a rat suffering from diabetes, and the aminoguanidine becomes remarkable as an agent for preventing diseases including diabetes mellitus (see "Science, vol. 232, p. 1629 (1986)"). However, the above-mentioned function of aminoguanidine is not always sufficient, and an agent achieving an anti-glycation effect satisfactory for practical use has not been found yet.
On the other hand, aldose reductase (AR) is known to be an enzyme for reducing aldoses such as glucose and galactose to polyols such as sorbitol and galactitol in a living body. It is also known that accumulation of the polyols thus produced by the enzyme in organs induces or exacerbates various diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, and therefore an inhibitor against this enzyme is useful as an agent for treating these diabetic complications.
Under these circumstances, the present inventors have synthesized various thiazolidines which are not disclosed in the above-mentioned literatures, and have studied their properties. As this result, the present inventors have found a compound having an anti-glycation effect and aldose-reductase inhibitory activities which were not exhibited by the above-mentioned known compounds. Thus, the present invention provides pyridine type thiazolidines capable of preventing or treating diabetes mellitus and diabetic complications.